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Biomedical subjects

B Wiedemann

Publications and source records attributed to B Wiedemann.

At least 91 records · Page 5Linked to original sources
PubMed1997

[30 years development of antibiotics].

Many new antibiotics with improved pharmacodynamic and pharmacokinetic properties have been developed in the last 30 years. This development, however, went down in the last five years. With modern techniques of sequencing of the complete bacterial genum in order to find new targest, with combinatory chemistry and with the high throughput screening about one new drug per year can be developed in the future. The activity of antibiotics is diminished by the increasing number of resistant strains and by the increase of infections with naturally resistant microorganisms. The rational use of antibiotics can slow down this trend and perhaps reverse it. To reach this aim it is necessary to increase research activities in the field of pharmacodynamics in order to allow a more rational dosing. Better technology documentation and statistics in microbiological diagnostics could improve calculated chemotherapy. Furthermore we need more information about the epidemiology of resistant bacteria, at least the knowledge about receptors, mechanism of action and mechanism of resistance should be known to circumvent these obstacles in antimicrobial chemotherapy.

Animals↗
PubMed1996

Syntheses and biological activities of new N1-aryl substituted quinolone antibacterials.

A series of quinolones with a systematically varied substitution at the phenyl ring at N1 has been synthesized. Three lipophilicity descriptors (log K, log P, Rm) and the pKa values have been determined as well as the microbiological activity: The MIC values for eight different strains of three Gram-positive and three Gram-negative species and the inhibitory concentrations of DNA supercoiling (IC90 and IC100) were determined. From a principal component and a QSAR analysis relationships between antibacterial activity concerning the whole-cell system and electronic properties as well as the length of the substituents at the phenyl rings could be derived. The activity in a cell-free system was governed by the lipophilicity and the width of the substituents. It is speculated that the quinolones take a defined place in the DNA gyrase-DNA complex which is characterized by polar amino acids. This is in agreement with findings from studies of mutant gyrases.

4-Quinolones↗
PubMed1996

The role of N-actylglucosaminyl-1,6 anhydro N-acetylmuramyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid-D-alanine for the induction of beta-lactamase in Enterobacter cloacae.

The mechanism of beta-lactamase induction in Enterobacter cloacae which is linked to the peptidoglycan recycling, was investigated by HPLC analysis of cell wall fragments in genetically defined cells. It is demonstrated here that the transmembrane protein AmpG transports not only the precursor muropeptide of M-tripeptide (N-acetylmuramyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid), the D-tripeptide (N-actylglucosaminyl-1,6 anhydro N-acetylmuramyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid), but also that of M-tetra-peptide (N-acetylmuramyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid-D-alanine), the D-tetrapeptide (N-actylglucosaminyl-1,6 anhydro N-acetylmuramyl-L-alanyl-D-glutamyl-meso-diaminopimelic acid-D-alanine), into the cytoplasm. These findings indicate that probably also M-tetrapeptide and D-tetrapeptide are signal muropeptides for beta-lactamase induction. In fact, D-tetrapeptide, not D-tripeptide, increases upon imipenem treatment.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1996

Location of N-acetylmuramyl-L-alanyl-D-glutamylmesodiaminopimelic acid, presumed signal molecule for beta-lactamase induction, in the bacterial cell.

Using a chromatographic method for the isolation and detection of periplasmic and cytoplasmic muropeptides avoiding radioactive labeling, we found that in the ampD-negative strain JRG582 the anhydromuropeptide N-acetylmuramyl-L-alanyl-D-glutamylmesodiaminopimelic acid (anhMurNAc tripeptide) accumulates not only in the cytoplasm but also in the periplasm. Simultaneously JRG582 carrying the Enterobacter cloacae genes ampC and ampR, which are necessary for the induction of beta-lactamase expression, overproduces beta-lactamase. We confirmed that the transmembrane protein AmpG transports a precursor muropeptide into the cytoplasm and that the formation of the anhMurNAc tripeptide takes place in the cytoplasm. anhMurNAc tripeptide can then be secreted into the periplasm. Therefore, the amount of anhMurNAc tripeptide in the cytoplasm is reduced not only by AmpD but also by transport out of the cell.

Acetylmuramyl-Alanyl-Isoglutamine↗
PubMed1996

Increased clearance of low density lipoprotein precursors in patients with heterozygous familial defective apolipoprotein B-100: a stable isotope approach.

In familial defective apolipoprotein B-100 (FDB) the presence of a mutant apolipoprotein (apo) B-100 (FDB3500Q/W) in LDL markedly reduces their affinity for the LDL receptor, leading to elevated LDL cholesterol levels. However, the hypercholesterolemia in most FDB patients is relatively mild when compared with, e.g., familial hypercholesterolemia (FH). In order to study mechanisms that may partly alleviate the clinical consequences of FDB, we investigated the in vivo kinetics of apoB-100-containing lipoproteins in five FDB heterozygotes (total cholesterol: 7.84 +/- 1.37 mmol/I; total apoB: 1.68 +/- 0.37 g/l; mean +/- SD) and six normolipidemic controls (4.61 +/- 0.62 mmol/l; 0.98 +/- 0.12 g/l) using a stable isotope approach. During and after a 10-12 h primed, constant infusion of either [13C6]phenylalanine or [2H3]leucine, tracer enrichment was determined in apoB-100 from ultracentrifugally isolated VLDL1 (Sf 60-400), VLDL2 (Sf 20-60), IDL (Sf 12-20), LDL1 (Sf 7-12), and LDL2 (Sf 0-7). The rates of apoB-100 production, catabolism, and transfer were estimated by model-based compartmental analysis. The overall fractional catabolic rate (FCR) of IDL apoB-100 in FDB was substantially increased (2.99 +/- 0.68 pools/day vs. 1.70 +/- 0.23 pools/day in controls, P < 0.01). The fractional rate of apoB-100 transfer from IDL to LDL in FDB was decreased (0.97 +/- 0.13 pools/day vs. 1.24 +/- 0.10 pools/day, P < 0.05). The FCR of LDL apoB-100 in FDB was decreased (0.18 +/- 0.07 pools/day vs. 0.56 +/- 0.05 pools/, P < 0.01). Finally, the input rate of LDL apoB-100 in FDB was markedly decreased (9.45 +/- 2.96 mg/kg day1 vs. 15.54 +/- 1.70 mg/kg day1, P < 0.05). Our data suggest that the relatively small increase of LDL concentrations in FDB is due to an increased clearance of LDL precursor particles via the LDL-receptor and apoE-receptors as well as a decreased conversion of IDL to LDL - two mechanisms that distinguish FDB from FH.

Adult↗
PubMed1995

Mathematical corrections for bacterial loss in pharmacodynamic in vitro dilution models.

In vitro dilution models are used to simulate in vivo drug concentration-time profiles and thus to study the effects of various antibiotic concentrations on the bacteria investigated. The major disadvantage of these models is permanent dilution of the bacterial culture, which falsifies the resulting kill curves. Known equations, which usually correct bacterial loss by simple first-order kinetics, do not take into account special test conditions, such as variable elimination rate constants, exceptionally long periods of investigation, or formation of biofilms. In the present investigation, we examined the validity of these equations with regard to the test conditions mentioned. We simulated the concentration-time curves resulting from continuous infusion of 1,000 mg of meropenem with steady-state levels of 2.5, 5.0, and 7.5 micrograms/ml in an in vitro dilution model. The resulting kill curves were compared with the kill curves obtained from incubation of bacteria in an undiluted system with meropenem at constant concentrations corresponding to the above-mentioned steady-state levels. Comparison of the matching kill curves showed that the common corrections, which do not consider the formation of biofilms in the compartments, partly overestimated the effect of bacterial dilution. We defined a factor, f, as an extension to the known equations which compensates for the effect of biofilms. Another extension was developed to allow the investigation of variable elimination rate constants. With the help of these extended mathematical corrections, we were able to fit the kill curves resulting from the in vitro dilution model exactly to the kill curves given by an undiluted system.

Bacteria↗
PubMed1995

[The intraoral bacterial colonization of temporary denture plastics].

Plastic materials used for temporary crowns and bridges in prosthetic dentistry are investigated with regard to the possibility of their microbial colonization. For this purpose four different kinds of materials, i.e. Resincap, Trim, Snap (Polyalcylmethacrylate) and Protemp (Bisphenol-A-Glycidyl-Methacrylate) were chose. With the help of 10 test persons in vivo experiments were carried out. After a period of two weeks it could be verified, that the bacteria have a stronger affinity to Protemp than to Polyalcylmethacrylate. The hypothesis, that the different intensity of colonization is due to the roughness of certain surfaces could be confirmed by additional experiments.

Crowns↗
PubMed1994

The negative regulator of beta-lactamase induction AmpD is a N-acetyl-anhydromuramyl-L-alanine amidase.

Construction of a malE-ampD gene fusion allowed purification of biologically active fusion protein by affinity chromatography. The cloned malE-ampD gene fusion complemented a chromosomal ampD mutation. Purified MalE-AmpD fusion protein was found to have murein amidase activity with a pronounced specificity for 1,6-anhydromuropeptides, the characteristic murein turnover products in Escherichia coli. Being a N-acetyl-anhydromuranmyl-L-alanine amidase AmpD is likely to be involved in recycling of the turnover products. It is suggested that the negative regulatory effect of AmpD is due to the hydrolysis of anhydro-muropeptides which may function as signals for beta-lactamase induction.

Base Sequence↗
PubMed1994

Mechanisms of quinolone resistance.

Two mechanisms of resistance to fluoroquinolones are known: (i) alteration of the molecular target of quinolone action-DNA gyrase, and (ii) reduction of the quinolone accumulation. Mutations altering the N-terminus of the gyrase A subunit, especially those around residues Ser83 and Asp87, significantly reduce the susceptibilities towards all quinolones, while alterations of the gyrase B subunit are rarely found and are of minor importance. Reduced drug accumulation is associated with alterations of the outer membrane protein profile in gram-negative bacteria. Such mutations include the marA locus in Escherichia coli and result in low level resistance towards quinolones and unrelated drugs. Increased activity of naturally existing efflux systems, such as the transmembrane protein NorA of staphylococci, may also lead to reduced accumulation in gram-positive and gram-negative bacteria. Clinical fluoroquinolone resistance is rarely found in intrinsically highly susceptible organisms such as Enterobacteriaceae and involves a combination of at least two mutations. In contrast, species with moderate intrinsic susceptibility such as Campylobacter jejuni, Pseudomonas aeruginosa, and Staphylococcus aureus require only one mutation to become clinically resistant. As a consequence development of resistance during therapy may result from acquisition of already resistant strains in the case of susceptible species, and selection of mutants in the case of less susceptible species.

Anti-Infective Agents↗
PubMed1994

Clinical significance and spread of fluoroquinolone resistant uropathogens in hospitalised urological patients.

The minimum inhibitory concentrations (MIC) of ciprofloxacin were determined for 441 uropathogens from patients with complicated and/or hospital acquired urinary tract infections (UTI). None of the Enterobacteriaceae was resistant (MIC > or = 4 mg/l), but 21.7% of enterococci, 28.3% of Pseudomonas spp. and 38.5% of staphylococci were. Subtyping of the strains revealed that with staphylococci there was no clonal spread of resistant strains. In the case of enterococci and Pseudomonas spp., however, cross infections played a major role (46% and 40% respectively). In a retrospective analysis of 370 UTI episodes caused by Pseudomonas aeruginosa (74), enterococci (185) or staphylococci (111) there was no difference between sensitive and resistant strains with respect to clinical aspects and rates of elimination by appropriate anti-bacterial therapy. The rates of spontaneous disappearance without antibacterial therapy ranged from 28% in the case of P. aeruginosa up to 63% in the case of coagulase-negative staphylococci. This implies that especially in UTI caused by gram-positive cocci an indication for antibacterial therapy should be weighted thoroughly and fluoroquinolones should only be used in accordance with sensitivity testing.

Anti-Infective Agents↗